Cigarette smoking is the major risk factor for the development of chronic bronchitis. Based on the knowledge that only 15 to 20% of chronic smokers develop significant airway disease, this proposal focuses on the identification of candidate genes linked to the risk of developing chronic bronchitis in association with cigarette smoking. We hypothesize that the stress of chronic cigarette smoking modulates the expression of antioxidant-related genes in the airway epithelium, but that for each gene, the response to smoking is variable among the population, resulting from inherent single polymorphisms (SNPs) in the antioxidant-related genes. Using fiberoptic bronchoscopy with airway epithelial brushing to obtain pure populations of airway epithelium, preliminary mRNA expression analysis of 54 antioxidant-related genes in phenotypically normal current smokers demonstrated that smoking significantly upregulated the expression of many of these genes. Importantly, there were differences in the extent of gene expression among the population, with different individuals up-regulating each gene in a variable fashion. Based on these observations and the knowledge that oxidants in cigarette smoking are a major mediator of airway disease, the proposal has the following specific aims. Aim 1 - to assess the hypothesis that there is differential expression of antioxidant-related genes in the large and small airway epithelium of phenotypically normal smokers and ex-smokers compared to matched individuals with predominant chronic bronchitis or predominant emphysema. Aim 2 - to evaluate the hypothesis that the differential expression of the antioxidant-related genes among phenotypically normal smokers and ex-smokers compared to matched individuals with emphysema and chronic bronchitis represent inherent genetic differences among these individuals that can be identified by single nucleotide polymorphisms (SNPs). Aim 3 - to use the set association method and haplotype analysis to integrate the gene expression and SNP data to identify a subset of the antioxidant-related alleles that represent risk factors for susceptibility to chronic bronchitis in response to smoking. [unreadable] [unreadable]